Mukhtar in Pharmacology of the Skin describes the communication between cells as being mediated by different biomolecules, such as hormones. These so called primary messengers bind to specific receptors on the cell surface. The binding of a primary messenger to its receptor conveys a certain information to the cell which is subsequently transduced through the membrane by a chain of signaling. This process involves various membrane structures and leads to the activation of an enzyme located at the intracellular side of the membrane. The stimulated enzyme generates a second messenger which evokes the cellular response; in most cases, by the activation of other enzymes. By these steps, the initial extracellular signal is converted into an intracellular signal. This process is called signal transduction.
The inositide cascade represents one of several signals transducing pathways. In its course, two second messengers, diacylglycerol (DG) and inositol triphosphate (IP 3)., are released. DG remains in the membrane and activates protein kinase C (PKC). IP 3 acts by releasing calcium ions from their intracellular stores. The calcium ions subsequently evoke the cellular response, mainly by activating a protein kinase (PKC)
Protein kinases regulate cellular responses by phosphorylation of substrate proteins (eg. receptors or enzymes) and thereby alter their state of activity. In the case of the inositide cascade, PKC mainly performs this reaction. Sphingosine dose-dependently inhibits PKC, but also binds to calmodulin (CaM) function and therefore inhibits CaM function. Keratinocyte intercellular adhesion molecule-1 (ICAM-1) is thought to be involved in dermal lymphocyte infiltration. The PKC activating phorbol ester, PMA has been reported to induce the expression of ICAM-1 in normal human keratinocytes. This effect can be blocked by a PKC inhibitor and suggests that PKC might play a regulatory role in ICAM-1 expression.
Psoriasis is characterized by a epidermal hyperproliferation and reduced cellular differentiation as well as inflammation. Experimental stimulation of PKC will produce a similar hyperproliferation. The release of reactive oxygen species (ROS) from human leucocytes represents an important part of the acute inflammation. Phorbol ester can induce the same cellular response and is mainly regulated by PKC. This pathway in psoriasis if stimulated by an activator of PKC, may account for epidermal inflammation.
PKC is known to function in cutaneous tumor promotion in that it represents the major cellular receptor for phorbol esters. PKC inhibitors like sphingosine inhibit phorbol ester-induced ornithine decarboxylase activity in the mouse skin.